Antifungal effects of a 1,3,4-thiadiazole derivative determined by cytochemical and vibrational spectroscopic studies

• Published in: PloS one Vol. 14; no. 9; p. e0222775
• Main Authors: Chudzik, Barbara, Bonio, Katarzyna, Dabrowski, Wojciech, Pietrzak, Daniel, Niewiadomy, Andrzej, Olender, Alina, Pawlikowska-Pawlęga, Bożena, Gagoś, Mariusz
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 30.09.2019; Public Library of Science (PLoS)
• Subjects: Analysis; Anesthesiology; Antibacterial agents; Anticancer properties; Antifungal activity; Antifungal agents; Antifungal Agents - chemical synthesis; Antifungal Agents - pharmacology; Aspergillus niger - chemistry; Aspergillus niger - drug effects; Aspergillus niger - isolation & purification; Aspergillus niger - ultrastructure; Azoles; Benzene; Biochemistry; Biological activity; Biology and Life Sciences; Biosynthesis; Biotechnology; Budding; Candida; Candida albicans - chemistry; Candida albicans - drug effects; Candida albicans - isolation & purification; Candida albicans - ultrastructure; Candida glabrata - chemistry; Candida glabrata - drug effects; Candida glabrata - isolation & purification; Candida glabrata - ultrastructure; Candida parapsilosis - chemistry; Candida parapsilosis - drug effects; Candida parapsilosis - isolation & purification; Candida parapsilosis - ultrastructure; Candida tropicalis - chemistry; Candida tropicalis - drug effects; Candida tropicalis - isolation & purification; Candida tropicalis - ultrastructure; Candidiasis - microbiology; Cell Line; Cell size; Cell Survival - drug effects; Cell Wall - chemistry; Cell Wall - drug effects; Cell Wall - ultrastructure; Cell walls; Cells (Biology); Chemical compounds; Chemistry; Chitin; Chitin - antagonists & inhibitors; Chitin - chemistry; Chitin - metabolism; Cytochemistry; Cytotoxicity; Diols; Disruption; Drug Resistance, Fungal - drug effects; Ergosterol; Fibroblasts; Fibroblasts - cytology; Fibroblasts - drug effects; Fungal infections; Fungi; Fungicides; Gastrointestinal system; Gastrointestinal tract; Giant cells; Glucan; Glucans; Glucans - antagonists & inhibitors; Glucans - chemistry; Glucans - metabolism; Glycols (Class of compounds); Heterocyclic compounds; Humans; Hydrocarbons; Medicine and Health Sciences; Microbial Sensitivity Tests; Molecular biology; Morphogenesis; Mycoses; Pharmacology; Physical Sciences; Phytosterols; Plant lipids; Polymerization; Proteins; Research and Analysis Methods; Rhodotorula - chemistry; Rhodotorula - drug effects; Rhodotorula - isolation & purification; Rhodotorula - ultrastructure; Septum; Skin; Spectroscopy; Substitutes; Thiadiazoles; Thiadiazoles - chemical synthesis; Thiadiazoles - pharmacology; Toxicity; Trichophyton - chemistry; Trichophyton - drug effects; Trichophyton - isolation & purification; Trichophyton - ultrastructure; Turgor; Yeast; United States; Poland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0222775

Compounds belonging to the group of 5-substituted 4-(1,3,4-thiadiazol-2-yl) benzene-1,3-diols exhibit a broad spectrum of biological activity, including antibacterial, antifungal, and anticancer properties. The mechanism of the antifungal activity of compounds from this group has not been described to date. Among the large group of 5-substituted 4-(1,3,4-thiadiazol-2-yl) benzene-1,3-diol derivatives, the compound 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol, abbreviated as C1, was revealed to be one of the most active agents against pathogenic fungi, simultaneously with the lowest toxicity to human cells. The C1 compound is a potent antifungal agent against different Candida species, including isolates resistant to azoles, and molds, with MIC100 values ranging from 8 to 96 μg/ml. The antifungal activity of the C1 compound involves disruption of the cell wall biogenesis, as evidenced by the inability of cells treated with C1 to maintain their characteristic cell shape, increase in size, form giant cells and flocculate. C1-treated cells were also unable to withstand internal turgor pressure causing protoplast material to leak out, exhibited reduced osmotic resistance and formed buds that were not covered with chitin. Disturbances in the chitin septum in the neck region of budding cells was observed, as well as an uneven distribution of chitin and β(1→3) glucan, and increased sensitivity to substances interacting with wall polymerization. The ATR-FTIR spectral shifts in cell walls extracted from C. albicans cells treated with the C1 compound suggested weakened interactions between the molecules of β(1→3) glucans and β(1→6) glucans, which may be the cause of impaired cell wall integrity. Significant spectral changes in the C1-treated cells were also observed in bands characteristic for chitin. The C1 compound did not affect the ergosterol content in Candida cells. Given the low cytotoxicity of the C1 compound to normal human dermal fibroblasts (NHDF), it is possible to use this compound as a therapeutic agent in the treatment of surface and gastrointestinal tract mycoses.